1. Field of the Invention
This application relates to polyorthoesters. In particular, this invention relates to bioerodible polyorthoesters containing amine groups and xcex1-hydroxy acid-containing groups.
2. Description of the Prior Art
Interest in synthetic biodegradable polymers for the systemic delivery of therapeutic agents began in the early 1970""s with the work of Yolles et al., Polymer News 1:9-15 (1970) using poly(lactic acid). Since that time, numerous other polymers have been prepared and investigated as bioerodible matrices for the controlled release of therapeutic agents.
U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344 and 4,180,646 disclose biodegradable or bioerodible polyorthoesters. These polymers are formed by a reaction between an orthoester (or orthocarbonate) such as 2,2-diethoxytetrahydrofaran and a diol such as 1,4-cyclohexanedimethanol. The reaction requires elevated temperature and reduced pressure and a relatively long reaction time. Drugs or other active agents are retained in the polymer matrix to be released as the polymer biodegrades due to hydrolysis of the labile linkages.
U.S. Pat. No. 4,304,767 discloses polymers prepared by reacting a polyol with a polyfunctional ketene acetal. These polymers represent a significant improvement over those of U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344 and 4,180,646, since synthesis proceeds readily at room temperature and atmospheric pressure, and the resulting polymers have superior properties.
Further polymers are disclosed in U.S. Pat. No. 4,957,998. These polymers contain acetal, carboxy-acetal and carboxy-ortho ester linkages, and are prepared by a two-step process beginning with the reaction between a polyfunctional ketene acetal and a compound containing a vinyl ether, followed by reaction with a polyol or polyacid.
Still further polymers of a similar type are disclosed in U.S. Pat. No. 4,946,931. The polymers are formed by a reaction between a compound containing a multiplicity of carboxylate functions and a polyfunctional ketene acetal. The resulting polymers have very rapid erosion times.
Despite the ease with which the orthoester linkage hydrolyses, polyorthoesters known in the prior art are extremely stable materials when placed in an aqueous buffer, or when residing in the body. This stability is attributable to the extreme hydrophobicity of the polyorthoesters which severely limits the amount of water that can penetrate the polymer. To achieve useful erosion rates, therefore, acidic excipients must be physically incorporated into the polymer. While this allows control over erosion rates, the physically incorporated acidic excipient can diffuse from the polymer matrix at varying rates, leaving a matrix that is completely depleted of excipient while the polymer still has a very long lifetime remaining.
U.S. Pat. Nos. 4,764,364 and 4,855,132 describe bioerodible polymers, in particular polyorthoesters containing an amine functionality. The polymers are said to erode more rapidly at lower pH than at higher pH in an acidic aqueous environment.
The disclosures of the documents listed in this section and elsewhere throughout this application are incorporated herein by reference.
In a first aspect, this invention is polyorthoesters of formula I or formula II: 
R* is a C1-4 alkyl;
R is a bond, xe2x80x94(CH2)axe2x80x94, or xe2x80x94(CH2)bxe2x80x94Oxe2x80x94(CH2)cxe2x80x94; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
n is an integer of at least 5; and
A is selected from R1, R2, R3, R4, and mixtures thereof, where
R1 is: 
where:
p is an integer of 1 to 20;
R5 is hydrogen or C1-4 alkyl; and
R6is: 
where:
s is an integer of 0 to 30;
t is an integer of 2 to 200; and
R7 is hydrogen or C1-4 alkyl;
R2 is: 
xe2x80x83R3is: 
where:
x is an integer of 0 to 30;
y is an integer of 2 to 200;
R8 is hydrogen or C1-4 alkyl;
R9 and R10 are independently C1-12 alkylene;
R11 is hydrogen or C1-6 alkyl and R12 is C1-6 alkyl; or R11 and R12 together are C3-10 alkylene; and
R4 is the residual of a diol containing at least one amine functionality incorporated therein;
in which at least 0.1 mol % of the A units are R1, and at least 0.1 mol % of the A units are R4.
In a second aspect, this invention is controlled release pharmaceutical compositions comprising:
(a) an active agent; and
(b) as a vehicle, the polyorthoester described above.
In a third aspect, this invention is a method of treating a disease state treatable by controlled release local administration of an active agent, such as treating pain by administration of a local anesthetic or treating cancer by administration of a chemotherapeutic or antineoplastic agent, comprising locally administering a therapeutically effective amount of the active agent in the form of the controlled release pharmaceutical composition described above.
In a fourth aspect, this invention is methods of preparation of the polyorthoesters of the first aspect of the invention and the controlled release pharmaceutical compositions of the second aspect of the invention.
It has now been discovered that polyorthoesters useful as orthopedic implants or vehicles for the sequestration and sustained delivery of drugs, cosmetic agents and other beneficial agents can be prepared in such a manner that the rate and degree to which they are hydrolyzed by contact with bodily fluids at normal body temperature and pH can be controlled without addition of exogenous acid. This discovery resides in the incorporation of esters of short-chain xcex1-hydroxy acids such as esters of glycolic acid, lactic acid or glycolic-co-lactic acid copolymer into the polyorthoester chain and variation of the amount of these esters relative to the polyorthoester as a whole.
In the presence of water, these esters, when incorporated into the polyorthoester chain, are readily hydrolyzed at a body temperature of 37xc2x0 C. and a physiological pH, in particular at a pH of 7.4, to produce the corresponding xcex1-hydroxy acids. The xcex1-hydroxy acids then act as an acidic excipient to control the hydrolysis rate of the polyorthoester. When the polyorthoester is used as a vehicle or matrix entrapping an active agent, the hydrolysis of the polyorthoester causes release of the active agent.
The use in these polyorthoesters of diols containing amine functionalities causes the polyorthoesters to become more pH-sensitive than polyorthoesters not containing such diols, and thus to hydrolyze yet more readily at lower pH than at higher pH. This is particularly so in an acidic aqueous environment, such as is found within animal cells, and enables the polyorthoesters to be relatively stable within the extracellular environment within an animal, such as within the blood, but to hydrolyze rapidly within the intracellular environment. This makes these polyorthoesters particularly suitable for delivery of active agents within the cell.
In addition, the mechano-physical state of the polyorthoester may also be controlled. This is achieved by the inclusion of the residues of certain diols in selected proportions relative to the polyorthoester as a whole. For example, a high content of the residue of 1,4-cyclohexane-dimethanol (as the trans isomer or as a cis/trans isomer mixture) or a similar xe2x80x9chardxe2x80x9d diol relative to a xe2x80x9csoftxe2x80x9d diol (definition of which is given below) produces a relatively rigid polymer chain and a more solid substance, and by decreasing the cyclohexanedimethanol content relative to the xe2x80x9csoftxe2x80x9d diol, the polyorthoester will change progressively through the stages of a rigid thermoplastic, a soft thermoplastic, a low melting solid to an ointment-like (viscous liquid) material, and any stage in between.
The polyorthoesters of the present invention are prepared by condensation reactions between diketene acetals and polyols, preferably diols, and the variation in mechano-physical state and rate of hydrolysis (bioerodibility) is achieved by the selection and use of combinations of different types of diols.
Definitions
xe2x80x9cActive agentxe2x80x9d includes any compound or mixture of compounds which produces a beneficial or useful result. Active agents are distinguishable from such components as vehicles, carriers, diluents, lubricants, binders and other formulating aids, and encapsulating or otherwise protective components. Examples of active agents are pharmaceutical, agricultural or cosmetic agents. Suitable pharmaceutical agents include locally or systemically acting pharmaceutically active agents which may be administered to a subject by topical or intralesional application (including, for example, applying to abraded skin, lacerations, puncture wounds, etc., as well as into surgical incisions) or by injection, such as subcutaneous, intradermal, intramuscular, intraocular, or intra-articular injection. Examples of these agents include, but not limited to, anti-infectives (including antibiotics, antivirals, fungicides, scabicides or pediculicides), antiseptics (e.g., benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, mafenide acetate, methylbenzethonium chloride, nitrofurazone, nitromersol and the like), steroids (e.g., estrogens, progestins, androgens, adrenocorticoids, and the like), therapeutic polypeptides (e.g. insulin, erythropoietin, morphogenic proteins such as bone morphogenic protein, and the like), analgesics and anti-inflammatory agents (e.g., aspirin, ibuprofen, naproxen, ketorolac, COX-1 inhibitors, COX-2 inhibitors, and the like), cancer chemotherapeutic agents (e.g., mechloreihamine, cyclophosphamide, fluorouracil, thioguanine, carmustine, lomustine, melphalan, chlorambucil, streptozocin, methotrexate, vincristine, bleomycin, vinblastine, vindesine, dactinomycin, daunorubicin, doxorubicin, tamoxifen, and the like), narcotics (e.g., morphine, meperidine, codeine, and the like), local anesthetics (e.g., the amide- or anilide-type local anesthetics such as bupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and the like), antiangiogenic agents (e.g., gombrestatin, contortrostatin, anti-VEGF, and the like), polysaccharides, vaccines, antigens, DNA and other polynucleotides, antisense oligonucleotides, and the like. The present invention may also be applied to other locally acting active agents, such as astringents, antiperspirants, irritants, rubefacients, vesicants, sclerosing agents, caustics, escharotics, keratolytic agents, sunscreens and a variety of dermatologics including hypopigmenting and antipruritic agents. The term xe2x80x9cactive agentsxe2x80x9d further includes biocides such as fungicides, pesticides, and herbicides, plant growth promoters or inhibitors, preservatives, disinfectants, air purifiers and nutrients.
xe2x80x9cAlkylxe2x80x9d denotes a linear saturated hydrocarbyl having from one to the number of carbon atoms designated, or a branched or cyclic saturated hydrocarbyl having from three to the number of carbon atoms designated (e.g., C1-4 alkyl). Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, cyclopropylmethyl, and the like.
xe2x80x9cAlkylenexe2x80x9d denotes a branched or unbranched saturated divalent radical having from one to the number of carbon atoms designated (e.g., C1-C12 alkylene). Examples of alkylene include methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), isopentylene (xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94), n-octylene (xe2x80x94(CH2)8xe2x80x94) and the like.
xe2x80x9cBioerodiblexe2x80x9d and xe2x80x9cbioerodibilityxe2x80x9d refer to the degradation, disassembly or digestion of the polyorthoester by action of a biological environment; including the action of living organisms and most notably at physiological pH and temperature. A principal mechanism for bioerosion of the polyorthoesters of the present invention is hydrolysis of linkages between and within the units of the polyorthoester.
xe2x80x9cComprisingxe2x80x9d is an inclusive term interpreted to mean containing, embracing, covering or including the elements listed following the term, but not excluding other unrecited elements.
xe2x80x9cControlled releasexe2x80x9d, xe2x80x9csustained releasexe2x80x9d, and similar terms are used to denote a mode of active agent delivery that occurs when the active agent is released from the delivery vehicle at an ascertainable and controllable rate over a period of time, rather than dispersed immediately upon application or injection. Controlled or sustained release may extend for hours, days or months, and may vary as a function of numerous factors. For the pharmaceutical composition of the present invention, the rate of release will depend on the type of the excipient selected and the concentration of the excipient in the composition. Another determinant of the rate of release is the rate of hydrolysis of the linkages between and within the units of the polyorthoester. The rate of hydrolysis in turn may be controlled by the composition of the polyorthoester and the number of hydrolyzable bonds in the polyorthoester. Other factors determining the rate of release of an active agent from the present pharmaceutical composition include particle size, acidity of the medium (either internal or external to the matrix) and physical and chemical properties of the active agent in the matrix.
xe2x80x9cMatrixxe2x80x9d denotes the physical structure of the polyorthoester which essentially retains the active agent in a manner preventing release of the agent until the polyorthoester erodes or decomposes.
xe2x80x9cSequestrationxe2x80x9d is the confinement or retention of an active agent within the internal spaces of a polyorthoester matrix. Sequestration of an active agent within the matrix may limit the toxic effect of the agent, prolong the time of action of the agent in a controlled manner, permit the release of the agent in a precisely defined location in an organism, or protect unstable agents against the action of the environment.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for that disease.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease). For the purposes of this invention, a xe2x80x9cdiseasexe2x80x9d includes pain.
A xe2x80x9cunitxe2x80x9d denotes an individual segment of a polyorthoester chain, which consists of the residue of a diketene acetal molecule and the residue of a polyol.
An xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d unit denotes a unit where A is R1, i.e. in which the polyol is prepared from an xcex1-hydroxy acid or cyclic diester thereof and a diol of the formula HOxe2x80x94R6xe2x80x94OH. The fraction of the polyorthoester that is xcex1-hydroxy acid containing units affects the rate of hydrolysis (or bioerodibility) of the polyorthoester, and in turn, the release rate of the active agent.
An xe2x80x9camine containingxe2x80x9d unit denotes a unit where A is R4, i.e. in which the diol contains an amine functionality. The fraction of the polyorthoester that is amine containing units affects the pH-sensitivity of the rate of hydrolysis (or bioerodibility) of the polyorthoester, and in turn, the release rate of the active agent.
xe2x80x9cHardxe2x80x9d and xe2x80x9csoftxe2x80x9d units denote individual units of the polyorthoester, the contents of which relative to the polyorthoester as a whole determine the mechano-physical state of the polyorthoester. xe2x80x9cHardxe2x80x9d units are units where A is R2 and xe2x80x9csoftxe2x80x9d units are units where A is R3.
xe2x80x9cVehiclexe2x80x9d and xe2x80x9ccarrierxe2x80x9d denote an ingredient that is included in a composition such as a pharmaceutical or cosmetic preparation for reasons other than a therapeutic or other biological effect. Functions served by vehicles and carriers include transporting an active agent to a site of interest, controlling the rate of access to, or release of, the active agent by sequestration or other means, and facilitating the application of the agent to the region where its activity is needed. Examples of vehicles and carriers include solids such as microparticles, microspheres, rods, and wafers; and semisolids that are dispensable by syringe or the like, or by spreading with a tool such as a spatula.
The polyorthoesters
The polyorthoesters are of formula I or formula II 
R is a bond, xe2x80x94(CH2)axe2x80x94, or xe2x80x94(CH2)bxe2x80x94Oxe2x80x94(CH2)cxe2x80x94; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
n is an integer of at least 5; and
A is selected from R1, R2 R3, R4, and mixtures thereof, where
R1 is: 
where:
P is an integer of 1 to 20;
R5 is hydrogen or C1-4 alkyl; and
R6 is: 
where:
s is an integer of 0 to 30;
t is an integer of 2 to 200; and
R7 is hydrogen or C1-4 alkyl;
R2 is: 
R3 is: 
where:
x is an integer of 0 to 30;
y is an integer of 2 to 200;
R8 is hydrogen or C1-4 alkyl;
R9 and R10 are independently C1-12 alkylene;
R11 is hydrogen or C1-16 alkyl and R12 is C1-6 alkyl; or R11 and R12 together are C3-10 alkylene; and
R4 is the residual of a diol containing at least one amine functionality incorporated therein; in which at least 0.1 mol % of the A units are R1, and at least 0.1 mol % of the A units are R4.
The structure of the polyorthoester useful for the present invention, as shown in formula I or formula II, is one of alternating residues of a diketene acetal and a diol, with each adjacent pair of diketene acetal residues being separated by the residue of one polyol, preferably a diol.
In the presence of water, the x-hydroxyacid containing units are readily hydrolyzed at a body temperature of 37xc2x0 C. and a physiological pH, to produce the corresponding hydroxyacids. These hydroxyacids then act as acidic catalysts to control the hydrolysis rate of the polyorthoester without the addition of exogenous acid. When the polyorthoester is used as a delivery vehicle or matrix entrapping an active agent, the hydrolysis of the polyorthoester causes release of the active agent.
Polyorthoesters having a higher mole percentage of the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d units will have a higher rate of bioerodibility. Preferred polyorthoesters are those in which the mole percentage of the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d units is in the range of about 0.1 to about 99 mole percent, such as about 0.5 to about 50 mole percent, more preferably from about 1 to about 30 mole percent, for example from about 5 to about 30 mole percent, especially from about 10 to about 30 mole percent.
Polyorthoesters having a higher mole percentage of the xe2x80x9camine containingxe2x80x9d units will have a rate of bioerodibility that is more pH-sensitive than non-xe2x80x9camine containingxe2x80x9d polyorthoesters, and increases at lower pH. Preferred polyorthoesters are those in which the mole percentage of the xe2x80x9camine containingxe2x80x9d units is in the range of about 0.1 to about 99.9 mole percent, more preferably from about 1 to about 80 mole percent, for example from about 5 to about 50 mole percent, especially from about 10 to about 30 mole percent.
Preferred polyorthoesters are those where:
n is an integer of about 5 to about 500, preferably about 20 to about 500, especially about 30 to about 300;
R5 is hydrogen or methyl;
R6 is: 
xe2x80x83where s is an integer of 0 to 10, especially 1 to 4; t is an integer of 2 to 30, especially 2 to 10; and
R7 is hydrogen or methyl;
R3 is: 
xe2x80x83where x is an integer of 0 to 10, especially 1 to 4; y is an integer of 2 to 30, especially 2 to 10; and
R8 is hydrogen or methyl;
R4 is selected from the residue (i.e. that part of the diol that is not the two hydroxy groups) of aliphatic diols of 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, interrupted by one or two amine groups, or is selected from the residue of di(hydroxy)- or bis(hydroxyalkyl)-cyclic amines, having from 4 to 20, preferably 4 to 10, carbon or nitrogen atoms between the hydroxy groups;
the amine groups are secondary or, preferably, tertiary amine groups;
the proportion of units in which A is R1 is about 0.5 to about 50 mole percent, more preferably from about 1 to about 30 mole percent, for example from about 5 to about 30 mole percent, especially from about 10 to about 30 mole percent; and
the proportion of units in which A is R4 is about 1 to about 80 mole percent, for example from about 5 to about 50 mole percent, especially from about 10 to about 30 mole percent.
While the presence of any of these preferences results in a polyorthoester that is more preferred than the same polyorthoester in which the preference is not met, the preferences are generally independent, and polyorthoesters in which a greater number of preferences is met will generally result in a polyorthoester that is more preferred than that in which a lesser number of preferences is met.
Expressed in terms of mole percent of the xe2x80x9chardxe2x80x9d unit relative to the polyorthoester as a whole, preferred polyorthoesters for liquid or semi-solid compositions are those in which the xe2x80x9chardxe2x80x9d unit constitutes about 20 mole percent or less. Likewise, preferred polyorthoesters for more solid compositions are those in which the xe2x80x9chardxe2x80x9d unit constitutes from about 30 mole percent to about 99.8 mole percent.
Polyorthoesters having a higher content of the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d unit will have a higher rate of bioerodibility.
With respect to the individual xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d unit, p is preferably 1 to 6, more preferably 1 to 4, most preferably 1 or 2; R5 is preferably hydrogen or methyl; and in the above definitions of R6, s is preferably 2 to 12, more preferably 2 to 6 and most preferably 2; and t is preferably 4 to 12, more preferably 4 to 6 and most preferably 6.
With respect to the individual xe2x80x9chardxe2x80x9d unit, R2 is preferably cyclohexanedimethanol.
With respect to the individual xe2x80x9csoftxe2x80x9d unit, in the definitions of R3, x is preferably 2 to 12, more preferably 2 to 6 and most preferably 2; y is preferably 4 to 12, more preferably 4 to 6 and most preferably 6; R8 is preferably hydrogen; R9 is preferably methyl; R10 is preferably hydrogen and R11 is preferably methyl.
With respect to the individual xe2x80x9camine containingxe2x80x9d unit, diols of the formula HOxe2x80x94R4xe2x80x94OH include aliphatic diols of 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, interrupted by one or two amine groups, and di(hydroxy)- or bis(hydroxyalkyl)-cyclic amines, having from 4 to 20, preferably 4 to 10, carbon or nitrogen atoms between the hydroxy groups; and the amine groups are secondary or, preferably, tertiary, amine groups.
Preparation of the Polyorthoesters
The polyorthoesters are prepared according to the methods described in U.S. Pat. Nos. 4,764,364, 4,855,132, and 5,968,543. Specifically, the polyorthoesters are prepared by the reaction of a diketene acetal of formula III or formula IV: 
where L is hydrogen or a C1-3 alkyl, with a diol of the formula HOxe2x80x94R1xe2x80x94OH and a diol of the formula HOxe2x80x94R4xe2x80x94OH, and optionally at least one diol of the formulae HOxe2x80x94R2xe2x80x94OH and HOxe2x80x94R3xe2x80x94OH.
To form the polyorthoester using a mixture of the various types of the diols, the mixture is formed with selected proportions based on the desired characteristics of the polyorthoester. The use of increasing amounts of diols in which A is R1 increases the bioerodibility of the polyorthoester, and the use of such diols in which R6 is a polyethyleneoxide moiety or an alkane increases the softness of the polymer; the use of increasing amounts of diols in which A is R2 increases the hardness of the polyorthoester; and the use of diols in which A is R3 increases the softness of the polyorthoester, especially when these diols are low molecular weight polyethylene glycols or aliphatic diols. The use of diols in which A is R4 increases the pH-sensitivity of the bioerodibility of the polyorthoester, increasing it particularly at low pH.
The preparation of the diketene acetals of the types of formula III and formula IV is disclosed in U.S. Pat. Nos. 4,304,767, 4,532,335, and 5,968,543; and will be known to a person of ordinary skill in the art. A typical method is the condensation of a bis(diol) of formula V (i.e. pentaerythritol) or formula VI: 
with two equivalents of a 2-halocarboxaldehyde dialkyl acetal, such as 2-bromoacetaldehyde diethyl acetal, followed by dehydrohalogenation to give the diketene acetal. The condensation of a glycol with diethylbromoacetals is described in Roberts et al., J. Am. Chem. Soc., 80, 1247-1254 (1958), and dehydrohalogenation is described in Beyerstedt et al., J. Am. Chem. Soc., 58, 529-553 (1936).
The diketene acetals may also be prepared by the isomerization of divinyl acetals. Thus, for example, 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU) may be prepared by the isomerization of 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane, using n-butyllithium in ethylenediamine. The isomerization of the double bond is described in Corey et al., J. Org. Chem., 38, 3224 (1973). The divinyl acetals may be prepared by the condensation of the bis(diol) of formula V or formula VI with two equivalents of a vinylic aldehyde, such as acrolein or crotonaldehyde, or their dialkyl acetals, such as acrolein dimethyl acetal, and such condensation reactions are well known.
The bis(diol) of formula VI where R is a bond is erytiritol. The bis(diol) of formula VI where R is xe2x80x94(CH2)axe2x80x94may be prepared by the oxidation of an xcex1,xcfx89-diene, such as 1,3-butadiene or 1,5-hexadiene, with an oxidizing reagent such as osmium tetroxide/hydrogen peroxide, or by other methods known in the art, to give the bis(diol). The bis(diol) of formula VI where R is xe2x80x94(CH2)bxe2x80x94Oxe2x80x94(CH2)cxe2x80x94 may be prepared by the reaction of an xcfx89-hydroxy-xcex1-olefin, such as allyl alcohol, with an xcfx89-haloalkyloxirane, such as epichlorohydrin, to form an xcfx89-epoxy-xcex1-olefin with the backbone interrupted by an oxygen atom, such as 2-allyloxymethyloxirane, which is then oxidized with an oxidizing reagent such as osmium tetroxide/hydrogen peroxide, or by other methods known in the art, to give the bis(diol).
The rigidity or flexibility of the polyorthoester is determined by the proportions of the xe2x80x9chardxe2x80x9d units and xe2x80x9csoftxe2x80x9d units in the polyorthoester structure, with greater rigidity achieved by including greater proportions of the xe2x80x9chardxe2x80x9d units in the polyorthoester.
The bioerodibility of the polyorthoester is determined by the proportion of the hydrolyzable xcex1-hydroxy acid ester groups, with greater bioerodibility achieved by including greater proportions of the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d units. The pH sensitivity of the bioerodibility is increased by the proportion of xe2x80x9camine containingxe2x80x9d units, with a greater proportion making the material more rapidly bioerodible at low pH.
Thus, both characteristics of the resulting polyorthoester prepared from the reaction between the diketene acetal of Formula III or formula IV and a mixture of the diols, are controlled by the ratio of quantities of the two to four types of diols in the diol mixture.
It is also understood that the present invention also encompasses cross-linked polyorthoesters which are prepared by employing one or more polyols having more than two hydroxy functional groups. Such cross-linked polyorthoesters may be prepared preferably by first reacting the diketene acetal with a diol in which A is R1, R2, R3, R4, or a mixture thereof, followed by addition of the polyol(s) having more than two hydroxy functional groups. Alternatively, the polyol(s) having more than two hydroxy functional groups may be added simultaneously with the diols. Polyols having more than two hydroxy functional groups suitable for the preparation of the cross-linked polyorthoesters may be the straight or branched chain type, including polyhydroxyl compounds such as 1,2,3-propanetriol, 1,2,5-pentanetriol, 1,2,6-hexanetriol, 1,3,5-pentanetriol, 1,2,4-butanetriol, 1,4,7-heptanetriol, 1,5,10-decanetriol, 1,5,12-dodecanetriol, 1,2,3,4,5,6-hexane-hexol, or such arnine-containing polyhydroxyl compounds as tris(2-hydroxyethyl)amine and the like. Other representative polyols of the type are described in U.S. Pat. No. 4,304,767. The reaction conditions (e.g, suitable solvents and reaction temperatures) and procedures for the preparation of the cross-linked polyorthoesters are similar to those described above for the preparation of the polyorthoesters employing only the diols, and are also described in U.S. Pat. Nos. 4,304,767 and 5,968,543.
The preparation of diols, in particular the diol of the formula HOxe2x80x94R3xe2x80x94OH is generally disclosed in Heller et al., J. Polymer Sci., Polymer Letters Ed. 18:293-297 (1980), by reacting an appropriate divinyl ether with an excess of an appropriate diol.
Diols of the formula HOxe2x80x94R4xe2x80x94OH are diols containing at least one secondary or, preferably, tertiary amine. They include diols where R4 is an amine such as Rxe2x80x2NRxe2x80x3Rxe2x80x2xe2x80x3 or Rxe2x80x2Nxe2x95x90Rxe2x80x2xe2x80x3 where each of Rxe2x80x2 and Rxe2x80x2xe2x80x3 is independently an aliphatic, aromatic, or aromatic/aliphatic straight or branched chain hydrocarbyl to which is bonded one of the hydroxy groups of the diol, and optionally where Rxe2x80x2 and Rxe2x80x2xe2x80x3 are bonded so that the amine is a cyclic amine, especially a straight or branched chain alkyl of 2 to 10 carbon atoms, and more especially 2 to 5 carbon atoms, and Rxe2x80x3 is hydrogen, C1-6 alkyl, C6-10 aryl, or aralkyl, especially alkyl, and more especially methyl. Other diols include those where two such amine groups are present, including in the same cyclic amine. Thus representative cyclic amine-based diols of the formula HOxe2x80x94R4xe2x80x94OH include di(hydroxy)- or bis(hydroxyalkyl)-substituted cyclic amines such as substituted pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, and the like. Some representative diols of the formula HOxe2x80x94R4xe2x80x94OH include N,N-bis(2-hydroxyethyl)amine, N,N-bis(2-hydroxyethyl)aniline, N-methyl-N,N-bis(2-hydroxyethyl)amine, N-butyl-N,N-bis(2-hydroxyethyl)amine, N-propyl-N,N-bis(2-hydroxyethyl)amine, N-2-propyl-N,N-bis(2-hydroxyethyl)amine, N-cyclohexyl-N,N-bis(2-hydroxyethyl)amine, N-benzyl-N,N-bis(2-hydroxyethyl)amine, 3-dimethylamino-1,2-propanediol, 3-(tert-butylamino)-1,2-propanediol, 1,4-bis(2-hydroxyethyl)piperidine, 1,4-bis(2-hydroxyethyl)piperazine, 1,4-bis(hydroxymethyl)piperazine, 7-(2,3 -dihydroxy-propyl)theophylline, 3,6-dihydroxypyridazine, 2,3-dihydroxypyridine, 2,4-dihydroxypyridine, 2,6-dihydroxypyridine, 4,6-dihydroxypyrimidine, N-ethyl-N,N-bis(2-hydroxyethyl)amine, and the like. Such diols include those containing both secondary and tertiary amines, though tertiary amines are preferred. Amine-containing polyols include N-3-hydroxypropyl-N,N-bis(2-hydroxyethyl)amine, 1,3-bis[tris(hydroxymethyl)methylamino]propane, 2,2-bis(hydroxymethyl)-2,2xe2x80x2,2xe2x80x3-nitrilotriethanol, tris(2-hydroxyethyl)amine, tris(3-hydroxypropyl)amine, and the like. These diols are known to the art in reported syntheses and many are commercially available.
Once made, the diol of the formula HOxe2x80x94R1xe2x80x94OH and the diol of the formula HOxe2x80x94R4xe2x80x94OH, and the optional diol(s) of the formulae HOxe2x80x94R2xe2x80x94OH and HOxe2x80x94R3xe2x80x94OH in the desired proportions are mixed with the diketene acetal of formula III or formula IV, in an approximately 1:1 ratio of total number of moles of diketene acetal to total number of moles of diols, in a suitable solvent at ambient temperature. The condensation reaction between the diketene acetal and the diols is carried out under conditions which are described in, for example, U.S. Pat. Nos. 4,764,364, 4,855,132, and 5,986,543, and are well known to those skilled in the art; and will also be readily apparent from the structures of the reactants themselves. Suitable solvents are aprotic solvents, such as dimethylacetamide, dimethyl sulfoxide, dimethylformamide, acetonitrile, acetone, ethyl acetate, pyrrolidone, tetrahydrofuran, and methylbutyl ether, and the like. Catalysts are not required for this reaction, but when used, suitable catalysts are iodine in pyridine, p-toluenesulfonic acid; salicylic acid, Lewis acids (such as boron trichloride, boron trifluoride, boron trichloride etherate, boron trifluoride etherate, stannic oxychloride, phosphorous oxychloride, zinc chloride, phosphorus pentachloride, antimony pentafluoride, stannous octoate, stannic chloride, diethyl zinc, and mixtures thereof); and Brxc3x8nsted catalysts (such as polyphosphoric acid, crosslinked polystyrene sulfonic acid, acidic silica gel, and mixtures thereof). A typical amount of catalyst used is about 0.2% by weight relative to the diketene acetal. Smaller or larger amounts can also be used, such as 0.005% to about 2.0% by weight relative to the diketene acetal. Once the reaction is complete, the reaction mixture is allowed to cool and concentrated by rotoevaporation under vacuum, for a semi-solid polyorthoester; or by precipitation in a non-solvent such as an alkanol (e.g. methanol, ethanol, and the like) or an alkane (e.g. hexanes, heptanes, and the like), for a solid polyorthoester. The polyorthoester may be further dried under vacuum at an elevated temperature.
The polyorthoesters may also be prepared by reaction of the diketene acetal with the chosen diol(s) under similar reaction conditions, but in the presence of a xe2x80x9cchain stopperxe2x80x9d (a reagent that terminates polyorthoester chain formation. Suitable chain stoppers are C5-20 alkanols, especially C10-20 alkanols. The chain stopper is preferably present in from 1-20 mol % based on the diketene acetal. The polyorthoesters thus prepared have lower molecular weights with a lower molecular weight dispersion than those prepared by the reaction of the diketene acetals with only diols.
The invention includes polyorthoesters which contain all four types of units as well as polyorthoesters containing from only the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d units and xe2x80x9camide containingxe2x80x9d units, or a mixture of these units with only one of the xe2x80x9chardxe2x80x9d units or xe2x80x9csoftxe2x80x9d units. It also includes polyorthoesters prepared from a mixture of units which contains two or more diols of the same type. It further includes polyorthoesters containing triols or higher polyols and/or xe2x80x9cchain stopperxe2x80x9d mono-alcohols, as described above.
Uses of the Polyorthoesters
The present polyorthoesters can be used for any use in which bioerodible polymers are usable, such as vehicles for the sustained release of an active agent.
To use the polyorthoester as a sustained-release vehicle or carrier, the active agent must be incorporated into a matrix of the polyorthoester or encapsulated within a capsule (or a xe2x80x9cmicrocapsulexe2x80x9d or xe2x80x9cnanocapsulexe2x80x9d, as those terms are sometimes used) of the polyorthoester. Methods for the preparation of sustained-release dosage forms using biodegradable polymers are well known in the art, as discussed in the references cited in the xe2x80x9cDescription of the Prior Artxe2x80x9d section of this application, and in other references familiar to those of ordinary skill in the art; so that a person of ordinary skill in the art would have no difficulty, having regard to that skill and this disclosure, in preparing sustained-release formulations using the polyorthoester of this invention. Suitable active agents include therapeutic agents such as pharmaceutical or pharmacological active agents, e.g. drugs and medicaments, as well as prophylactic agents, diagnostic agents, and other chemicals or materials useful in preventing or treating disease. The compositions of this invention are particularly useful for the therapeutic treatment of humans and other mammals, but may also be used for other animals. In addition, the sustained-release compositions of this invention may also be used for the release of cosmetic and agricultural agents, or for the release of biocides, such as fungicides or other pesticides, into an environment where prolonged release of the active agent is desired.
In the case of matrix formulations, the polyorthoester is first mixed with the active agent. High homogeneity may be achieved by mixing the polyorthoester in its heat softened state with the active agent, followed by lowering the temperature to harden the composition. Alternatively, the polyorthoester can be dissolved in an appropriate casting solvent, such as tetrahydrofuran, methylene chloride, chloroform or ethyl acetate, and the active agent can then be dispersed or dissolved in the polyorthoester solution, followed by evaporating the solvent to achieve the finished composition. Another method is grinding a solid polyorthoester material into powder which is then mixed with a powdered active agent. The active agent may also be incorporated into the mixture of monomers before polymerization provided that it is stable under the polymerization conditions and does not interfere with the polymerization reaction.
If the active agent is one that is unstable at elevated temperatures (e.g. above 40xc2x0 C.), or in the presence of organic solvents or organic solvent/water mixtures, such as a protein, then special preparation techniques may be required to minimize the exposure of the active agent to damaging conditions. Such techniques are disclosed in, for example, U.S. Pat. No. 5,620,697 (Txc3x6rmxc3xa4lxc3xa4 et al., assigned to Orion-Yhtyma Oy and Leiras Oy), which discloses ultrasonic melting to form matrix-type pharmaceutical compositions, and U.S. Pat. No. 5,518,730 (Fuisz, assigned to Fuisz Technologies, Inc.), which discloses melt-spinning, both of which techniques are designed to minimize the exposure of the polymer and active to elevated temperatures. Other methods are disclosed in the patents and literature references cited elsewhere in this application.
An alternate method for the incorporation and release of sensitive therapeutic agents is to use bioerodible polyorthoesters that have physical properties tailored for this incorporation. For example, the polyorthoester may be chosen so that it is semi-solid and has an ointment-like consistency, rather than being fully solid.
The composition obtained from any of the above methods can be readily processed into a variety of shapes and forms for implantation, insertion or placement on the body or into body cavities or passageways. For example, the polyorthoester composition may be injection molded, extruded or compressed into a thin film or made into devices of various geometric shapes or forms such as flat, square, round, cylindrical, tubular, disc, ring and the like. Rod- or pellet-shaped devices may be implanted through a trocar, such as is known for Norplant(copyright) implants, and these or other shapes may be implanted by minor surgical procedures. Alternatively, a device may be implanted following a major surgical procedure such as tumor removal in the surgical treatment of cancer.
The polyorthoester composition may also be injected by syringe subcutaneously or intramuscularly as particles of 0.1 xcexcm to 1000 xcexcm, preferably 0.5 xcexcm to 200 xcexcm, and more preferably 1 xcexcm to 150 xcexcm suspended in a pharmaceutically acceptable injection base. Liquid vehicles useful for suspending the drug-polyorthoester composition for injection include isotonic saline solution or oils (such as corn oil, cottonseed oil, peanut oil and sesame oil) which, if desired, may contain other adjuvants.
Another injectable dosage form may be prepared from an active agent mixed in a polyorthoester of the present invention which has an semi-solid consistency or which, when mixed with a suitable liquid excipient, forms a semi-solid composition such as the compositions described in U.S. patent application Ser. No. 09/854,180. Such a dosage form may be administered by injection. Such a dosage form may also be administered by direct application to an area to be treated, such as by spreading into a wound with a spatula.
The polyorthoester composition administered by either injection or implantation undergoes bioerosion in the body into non-toxic and non-reactive materials. By controlling the number of hydrolyzable bonds in the polyorthoester, the active agent may be released at a desired rate. Implants prepared from the present polyorthoesters in which the polyorthoester constitutes the matrix containing an active agent also have the advantage that they do not require removal because of the bioerodibility of the polyorthoester.
In some cases, particles with cores of the pure active agent coated with various thicknesses of the present polyorthoester may be preferred for sustained delivery of the active agent. Coating or encapsulation of discrete particles of the active agent may be accomplished by conventional methods which are all well-known to the person skilled in the art. For example, finely divided drug particles may be suspended in a solvent system (in which the drug is not soluble) containing the dissolved polyorthoester and other excipients, followed by spray drying. Alternatively, the drug particles may be placed in a rotating pan or a fluid-bed dryer and the polyorthoester dissolved in a carrier solvent is sprayed onto the drug particles until a suitable coating quantity is deposited on the particles to give a desired thickness. The coating may also be achieved by suspending the drug particles in a solvent system containing the dissolved polyorthoester followed by adding to the suspension a non-solvent causing the polyorthoester to precipitate and form a coating over the drug particles.
For the sustained release compositions, because the active agent will be released over a controlled period of time, the agent usually is present in an amount which is greater than the conventional single dose. The relative proportions of the active agent and the polyorthoester can vary over a wide range (e.g., 0.1 to 50 weight percent) depending on the therapeutic agent and the desired effect.
Sustained compositions of cosmetic and agricultural agents may also be prepared by any one of the methods as described above, using the polyorthoesters of the present invention.
The solid polyorthoesters (those containing a high percentage of the xe2x80x9chardxe2x80x9d unit and/or a high proportion of the xe2x80x9chydrogen bondingxe2x80x9d unit) are also useful for a variety of orthopedic applications. For example, they can be used as fracture fixation devices for repair of osteochondral defects, ligament and tendon reconstructions and bone substitutes. In addition, the fact that the present polyorthoesters permit simultaneous selection of both a desired level of their mechano-physical state and a desired rate of bioerodibility, also renders them attractive as grafts or scaffolds on which cells can be cultured in vitro prior to implantation to regenerate tissues. Tissues which can be regenerated using this approach include but not limited to, bone, tendon, cartilage, ligaments, liver, intestine, ureter and skin tissues. For example, the polyorthoesters may be used to regenerate skin for patients with bums or skin ulcers. Cartilages may be repaired by first isolating chondrocytes from a patient (or a donor), allowing them to proliferate on the scaffolds prepared from the present polyorthoester and re-implanting the cells in the patient.
The polyorthoester scaffolds or implants may further contain other biologically active substances or synthetic inorganic materials such as reinforcing filler material for enhancing the mechanical properties of the scaffolds or implants (e.g. calcium sodium metaphosphate fibers), antibiotics or bone growth factors to induce and/or promote orthopedic restoration and tissue regeneration.
The compositions are also stable. The release rates of the active agent are not significantly affected by irradiation for sterilization.
Particular Compositions and their Uses
Exemplary compositions of this invention, and their uses, include:
(1) compositions containing local anesthetics, optionally in combination with glucocorticosteroids such as dexamethasone, cortisone, hydrocortisone, prednisone, prednisolone, beclomethasone, betamethasone, flunisolide, fluoconolone acetonide, fluocinonide, triamcinolone, and the like, for the prolonged relief of local pain or a prolonged nerve blockade;
(2) compositions containing cancer chemotherapeutic agents, such as those listed above under xe2x80x9cActive Agentsxe2x80x9d, for deposition by syringe or by injection into tumors or operative sites from which a tumor has been ablated, for tumor control or treatment and/or the suppression of regrowth of the tumor from residual tumor cells after ablation of the tumor;
(3) compositions containing progestogens, such as flurogestone, medroxyprogesterone, norgestrel, norgestimate, norethindrone, and the like, for estrus synchronization or contraception;
(4) compositions containing antimetabolites such as fluorouracil and the like, as an adjunct to glaucoma filtering surgery; compositions containing antiangiogenic agents such as combrestatin, for the treatment of macular degeneration and retinal angiogenesis; and other compositions for the controlled release of ophthalmic drugs to the eye;
(5) compositions containing therapeutic polypeptides (proteins), such as insulin, LHRH antagonists, and the like, for the controlled delivery of these polypeptides, avoiding the need for daily or other frequent injection;
(6) compositions containing anti-inflammatory agents such as the NSAIDs, e.g. ibuprofen, naproxen, COX- 1 or COX-2 inhibitors, and the like, or glucocorticosteroids, for intra-articular injection;
(7) compositions containing antibiotics, for the prevention or treatment of infection, especially for deposition into surgical sites to suppress post-operative infection, or into or on wounds, for the suppression of infection (e.g. from foreign bodies in the wound);
(8) compositions containing morphogenic proteins such as bone morphogenic protein; and
(9) compositions containing DNA or other polynucleotides, such as antisense oligonucleotides.